Wednesday, May 8, 2024
5/8/2024
PROJECT SUMMARY Our recent work identifying C. acnes-induced T cell extracellular traps (TETs) employed novel technologies and in-so-doing made several critical observations, that C. acnes phylotypes can drive the differentiation of TH17 cell into either antimicrobial or non-antimicrobial TH17 cells. In turn, antimicrobial TH17 cells release TETs that entangle and kill bacteria. These observations, along with supporting publications, leads directly to this proposal. Importantly, while this proposal has major implications in improving our understanding of T cell-microbe interactions, it is purposefully designed to interrogate the mechanisms by which C. acnes phylotypes activate T cell subsets to release mitochondria-derived extracellular traps (mtETs) both broadly and mechanistically through innovative translational research as a critical next step. To achieve its goals, this grant builds on ample preliminary findings of i) confocal live imaging demonstrating a catapult-like release of mtETs independent of T cell death, and ii) single cell RNA sequencing data (scRNA-seq) showing elevated expression of mitochondrial- associated genes in T cell subsets from acne lesions but not in nonlesional skin. The mechanisms governing the induction, release and the role of mtETs in acne are unknown . Our central hypothesis is that C. acnes-induced T cell extracellular trap formation involves multiple mechanisms that either ameliorate or potentiate the inflammatory response in acne. To test this, we will determine the mechanism by which C. acnes induce mtETs release from T cells (Aim 1), and identify proteins associated with mtETs including their antimicrobial activity against C. acnes (Aim 2). Our strategy will include: classical immunological techniques involving T cell cloning to dissect the immune effector functions that underlie T cell-mediated antimicrobial host defense; confocal live imaging to define mechanisms of mtETs release and mitochondrial dynamics during mtETs formation; Mass spectrometry analysis to determine protein composition of mtETs and state-of-the-art scRNA-seq experiments to compute mitochondrial gene signatures and to define the T cell subsets and immune circuits present in acne lesions. This contribution is critical as, our studies will make significant conceptual advances in understanding how C. acnes phylotypes shape T cell immune responses in acne skin. The identification of inflammatory and/or antimicrobial proteins associated with mtETs can ultimately guide the design of new “druggable” host targets to ameliorate inflammatory acne and other skin diseases caused by dysbiosis.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
